Signal Transduct Target Ther. 2026 Sep 03. pii: 362. [Epub ahead of print]11(1):
T cell exhaustion and T cell senescence constitute distinct yet partially overlapping differentiation states that collectively constrain T cell functionality. T cell exhaustion arises under conditions of chronic antigen exposure and is characterised by a progressive, hierarchical loss of effector capacity, sustained expression of inhibitory receptors, and extensive transcriptional, epigenetic and metabolic reprogramming. By contrast, T cell senescence represents a more stable and terminal state, driven by replicative history, age-associated decline or stress-induced damage, and is defined by durable cell cycle arrest, altered differentiation, metabolic remodelling and acquisition of a pro-inflammatory secretory phenotype. In the context of cancer, dysfunctional T cells contribute to tumour progression, while also representing a major barrier to the success of T cell-based immune therapies, which strongly rely on the fitness, persistence and functional plasticity of T cells. Although substantial efforts have focused on overcoming exhaustion and optimising T cell manufacturing, senescence remains comparatively underexplored and presents unique therapeutic challenges due to its relative resistance to functional reprogramming. This review provides a comprehensive overview of T cell replenishment in homeostasis, followed by the molecular hallmarks and signalling pathways of T cell senescence and exhaustion. We discuss the current landscape of T cell-based immune therapies, including immune checkpoint blockade, T cell engagers and adoptive cell therapies, and explain how T cell dysfunction impacts their therapeutic outcomes. Finally, we highlight emerging strategies to prevent or overcome T cell dysfunction in adoptive cell therapy products.